The goal of any drug delivery system is to provide a therapeutic amount of a drug to the site in the body which is the intended target for drug therapy and to maintain a desired drug concentration for the time required to achieve a desired result. The two most important aspects of this goal are targeting of the drug to a specific organ or tissue (spatial placement) and controlling the rate of drug delivery (and hence the concentration at the target) to the target (temporal delivery).
The family of peptides known as transforming growth-factor type .beta. (TGF-.beta.), including TGF-.beta.1 and TGF-.beta.2, regulates cell growth and differentiation. These growth-regulatory polypeptides can both stimulate and inhibit cell proliferation, depending largely on the cell type. TGF-.beta.1 and TGF-.beta.2 have a common antiproliferative effect, for example, on epithelial cell growth, as well as a high degree of receptor cross-reactivity. Thus a degree of spatial placement may be achieved in controlling cell growth, in particular tumor cell growth, while minimizing effects on normal cells by use of such growth factors as antiproliferative agents. However, the half-life of the growth factor TGF-.beta., when administered by conventional means is on the order of 2 to 5 minutes due to, for example, degradative enzymatic activity or elimination via binding to serum binding proteins. Thus, the temporal delivery of these polypeptides is difficult to control.
To achieve spatial placement of a drug, a number of systems have been proposed. These include the use of targeted delivery systems such as nanoparticles, liposomes, and resealed erythrocytes, as well as the use of compositions which comprise a targeting portion, suck as an antibody to a specific cellular antigen, and a therapeutic portion, for example, a cytotoxic agent. Some spatial placement may also be achieved in specialized situations, such as the use of intraocular devices and intravaginal and intrauterine devices. Spatial placement may also be achieved by using drugs or naturally occurring compounds which have a higher affinity for one type of cell as opposed to another, for example, steroid or peptide hormones and congers thereof, which interact with specific receptors in/on the target cell.
Temporal delivery of a drug is not well controlled by conventional drug dosage forms (such as solutions, suspensions, capsules, tablets, emulsions, aerosols, films, ointments and suppositories). The rate-limiting step in delivery of drug to its target area is generally absorption of the drug across a biological membrane, such as the intestinal epithelium or the endothelial cell lining of the vasculature. One means of prolonging the bioavailability of an administered composition is to provide it in a form in which it may readily permeate across a cell membrane. An alternate means is to provide for nonimmediate release from the dosage form, so that release of the drug becomes the rate-limiting step in delivery of the drug to a specific target area. Nonimmediate-release delivery systems may take several forms, including sustained-release systems where the drug-delivery system slowly releases the drug over an extended period of time.
Use of a sustained-release system can improve the bioavailability of compounds such as polypeptides which are susceptible to enzymatic inactivation. The sustained-release system can be used locally, which can provide further for selective inhibition of cell proliferation since concentration of drug at the target site will be high, but the systemic concentration will be low. This is particularly advantageous for drugs which have a low therapeutic index since potential side effects are reduced by the-use of sustained-release systems. Lower total amounts of drug may be used, preferably less than the LD.sub.50 of the drug. Thus it is of interest to develop methods and compositions for selective inhibition of cell proliferation by the use of a drug delivery system which provides both spatial placement and temporal delivery of growth factors having anti-proliferative activity. Such delivery systems can provide a more effective treatment yet achieve an antiproliferative effect at lower total drug concentrations.